Project Summary/Abstract Due to the relationships between loneliness and a variety of poor health outcomes and mortality, loneliness is increasingly being recognized as an important public health issue. Despite the relevance of loneliness for health, including evidence suggesting the effects may be particularly pronounced for middle- aged adults, loneliness is a highly understudied topic in mid-life in need of further research. One potential mechanism for the effect of loneliness on health is inflammation. Lonely individuals have heightened inflammation, and inflammation can increase feelings of loneliness. Furthermore, loneliness and inflammation share similar psychological states, both marked by hypersensitivity to the social world, including increased sensitivity to both negative and positive social cues (i.e., social threat and social reward). Thus, by breaking the cycle between inflammation and loneliness, and altering the underlying hypersensitive psychological state, it is possible that an anti-inflammatory drug may lead to improvements in loneliness. However, to our knowledge, no studies have explicitly tested this. The objective of this NIA R21 application is to address this gap in the literature and test the effect of an anti-inflammatory medication on loneliness in a sample of middle-aged adults and to examine the social psychological mechanisms that may underlie any benefits. Participants (ntotal=100; aged 45-59) will be randomly assigned to receive naproxen (a nonsteroidal anti-inflammatory drug) or placebo for four weeks. Pre- and post-intervention, participants will complete self-report measures of loneliness, physical, and mental health, as well as experimental tasks intended to assess sensitivity to both social threat and social reward, as well as desire to socially engage with others. Participants will also have blood drawn to assess inflammation. It is hypothesized that naproxen (vs. placebo) will lead to decreases in feelings of loneliness via dampening of social threat and social reward systems. Furthermore, it is hypothesized that naproxen will lead to increased interest in social re-engagement. We will also explore whether these effects are mediated by changes in inflammatory pathways as well as whether these changes persist past the end of the intervention. The present study will aid in our understanding of the relationship between loneliness and inflammation, particularly in middle-aged adults where this relationship is understudied and could be especially impactful. Moreover, it will provide insight into how we can target biological processes such as inflammation in order to improve loneliness, an important psychosocial factor with far-reaching effects on heath outcomes.